Wearable microneedles-based extended gate field-effect transistor for real-time detection of biomarkers from interstitial fluid

Abstract

The present disclosure provides a device and system for detecting and/or measuring a constituent of an interstitial fluid from the skin of a subject. The device is a wearable extended gate field effect transistor (EGFET) device comprising a polymeric substrate for fixing to the skin of the subject: an extended gate electrode comprising a first microneedle configured for accessing the interstitial fluid and a first electric contact, wherein the first microneedle and the first electric contact are disposed on the polymeric substrate; and a field effect transistor (FET) associated with the first microneedle through the first electric contact. Further provided are a method for detecting and/or measuring a constituent of an interstitial fluid from the skin of a subject involving the use of the system and a method for fabricating the EGFET device.

1 - 48 . (canceled) 
     
     
         49 . A wearable extended gate field effect transistor (EGFET) device for detecting and/or measuring a constituent of an interstitial fluid from the skin of a subject, the device comprising:
 (a) a polymeric substrate for fixing to the skin of the subject;   (b) an extended gate electrode comprising a first microneedle configured for accessing the interstitial fluid and a first electric contact, wherein the first microneedle and the first electric contact are disposed on the polymeric substrate;   (c) a reference electrode comprising a second microneedle and a second electric contact, wherein the second microneedle and the second electric contact are disposed on the polymeric substrate; and   (d) a field effect transistor (FET) associated with the first microneedle through the first electric contact,   wherein a portion of the polymeric substrate on which the first electric contact is disposed is stretchable.   
     
     
         50 . The device according to  claim 49 , wherein the second electric contact is disposed on the stretchable portion of the polymeric substrate, or wherein the first microneedle is solid; and/or wherein the second microneedle is solid. 
     
     
         51 . The device according to  claim 49 , wherein the polymeric substrate has a thickness gradient between the first microneedle and the first electric contact, and/or wherein the thickness of a portion of the polymeric substrate on which the first microneedle is disposed is at least 50% higher than the thickness of a portion of the polymeric substrate on which the first electric contact is disposed. 
     
     
         52 . The device according to  claim 51 , wherein the portion of the polymeric substrate on which the first microneedle is disposed is substantially rigid and the stretchable portion of the polymeric substrate on which the first electric contact is disposed is flexible, and/or wherein the portion of the polymeric substrate on which the first microneedle is disposed and the portion of the polymeric substrate on which the first electric contact is disposed are made of the same polymeric material. 
     
     
         53 . The device according to  claim 49 , wherein the polymeric substrate is made of a polymeric material selected from the group consisting of styrene-block-isoprene-block styrene (SIS), 1-styrene-butadiene-styrene block copolymer (SBS), 2-styrene ethylene butylene styrene block copolymer (SEBS), polydimethylsiloxane (PDMS), polybutadiene rubber, polyurethane thermoplastic elastomer, low-density polyethylene (LDPH), polyisoprene, chloroprene rubber (CR), silicone rubber, and combinations and derivatives thereof. 
     
     
         54 . The device according to  claim 49 , wherein the first microneedle, the second microneedle or both are made of a material selected from the group consisting of a polymer, metal, metal alloy, carbon, and combinations thereof. 
     
     
         55 . The device according to  claim 54 , wherein the polymer is selected from the group consisting of polyester, polystyrene, polycarbonate, poly (methyl methacrylate), acrylate, polyvinylpyrrolidone, epoxy-based negative photoresist, and combinations thereof; and/or wherein the first microneedle is made of polystyrene, coated by a metal selected from Au, Pt, and Ni. 
     
     
         56 . The device according to  claim 54 , wherein the first microneedle is modified with a biorecognition element selected from the group consisting of an enzyme, antibody, aptamer, ion-selective membrane (ISM), protonically doped polymer, DNA, ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), molecularly imprinted polymer (MIP), and combinations thereof. 
     
     
         57 . The device according to  claim 56 , wherein the biorecognition element is bound to the first microneedle via a linker or is held within a supporting film or matrix, and/or wherein said constituent is a sodium ion and the biorecognition element comprises Na ionophore X and sodium tetrakis [3,5-bis(trifluoromethyl)phenyl] borate (Na-TFPB). 
     
     
         58 . The device according to  claim 57 , wherein the biorecognition element is immobilized on the first microneedle by polyvinyl chloride (PVC) and bis(2-ethylehexyl) sebacate (DOS), and/or wherein said constituent is cortisol and the biorecognition element comprises monoclonal anti-cortisol. 
     
     
         59 . The device according to  claim 58 , wherein the biorecognition element is immobilized on the first microneedle via a (3-aminopropyl)triethoxysilane (APTES) and glutaraldehyde linker. 
     
     
         60 . The device according to  claim 56 , wherein said constituent is glucose and the biorecognition element is glucose oxidase. 
     
     
         61 . The device according to  claim 60 , wherein the biorecognition element is immobilized on the first microneedle by chitosan, wherein chitosan is mixed with carbon nanotubes. 
     
     
         62 . The device according to  claim 56 , wherein said constituent is a hydronium ion and the biorecognition element is polyaniline (PANI). 
     
     
         63 . The device according to  claim 54 , wherein the second microneedle is made of polystyrene coated by Ag, or wherein the second microneedle is made of polystyrene coated by Ag and modified with a metal material configured to apply voltage on the surface of the second microneedle, the gate voltage of the FET being responsive to the metal material. 
     
     
         64 . The device according to  claim 63 , wherein the metal material is selected from the group consisting of Ag/AgCl/PVB and Au. 
     
     
         65 . The device according to  claim 49 , wherein the first microneedle, the second microneedle or both have a conical shape having a height between about 250 μm and about 5 mm and a diameter at its base between about 100 μm and 2.5 mm. 
     
     
         66 . The device according to  claim 49 , wherein the extended gate electrode comprises a plurality of first microneedles disposed on the polymeric substrate and arranged in an array, wherein the FET is associated with the plurality of first microneedles through the first electric contact, and/or wherein the reference electrode comprises a plurality of second microneedles disposed on the polymeric substrate and arranged in an array. 
     
     
         67 . The device according to  claim 49 , wherein the first electric contact, the second electric contact or both comprise electrically conductive elongated nanostructures. 
     
     
         68 . The device according to  claim 67 , wherein the electrically conductive elongated nanostructures are selected from the group consisting of nanotubes, nanowires, nanoribbons, nano-whiskers, nanostrips, nanorods, and combinations thereof, and/or wherein the electrically conductive elongated nanostructures are made of a material selected from the group consisting of a metal, metal alloy, carbon, and combinations thereof; and/or wherein the first electric contact and the second electric contact comprises silver nanowires (AgNWs). 
     
     
         69 . The device according to  claim 49 , wherein the FET is selected from the group consisting of a metal-oxide-semiconductor field-effect transistor (MOSFET), junctionless nanowire transistor (JLNT), metal-nitride-oxide-semiconductor transistor (MNOS), junction field-effect transistor (JFET), static induction transistor (SIT); heterostructure insulated-gate field-effect transistor (HIGFET), modulation-doped field-effect transistor (MODFET); tunnel field-effect transistor (TFET), high-electron-mobility transistor (HEMT), metal-semiconductor field-effect transistor (MESFET), nanoparticle organic memory field-effect transistor (NOMFET), graphene nanoribbon field-effect transistor (GNRFET), vertical-slit field-effect transistor (VeSFET), carbon nanotube field-effect transistor (CNTFET), organic field-effect transistor (OFET), quantum field effect transistor (QFET), Schottky-barrier field-effect transistor (SB-FET), and graphene-based field effect transistor (GFET). 
     
     
         70 . A system for detecting and/or measuring a constituent of an interstitial fluid from the skin of a subject, the system comprising:
 the wearable EGFET device according to  claim 49 ; and   at least one of:
 a control unit being in electrical communication with the EGFET device, which measures an electrical signal generated by the FET in response to an interaction between the first microneedle and said constituent; and 
 a transmitter, which receives the electrical signal generated by the FET in response to the interaction between the first microneedle and said constituent and transmits said signal to a remote server and/or to a portable electronic device. 
   
     
     
         71 . The system according to  claim 70 , wherein the control unit is in electrical communication with each one of the FET, extended gate electrode, and reference electrode within the EGFET device, and/or wherein the system further comprises a display unit in electrical communication with the control unit for displaying information related to the measuring of the electrical signal, and/or means for determining concentration of the constituent in the interstitial fluid upon receipt of the electrical signal. 
     
     
         72 . A method for detecting and/or measuring a constituent of an interstitial fluid from the skin of a subject, the method comprising:
 (a) providing the system of  claim 70 ;   (b) fixing the wearable EGFET to the skin of a subject, thereby enabling an interaction between the first microneedle and said constituent;   (c) measuring an electrical signal generated by the FET in response to the interaction between the first microneedle and said constituent; and   (d) analyzing the electrical signal by at least one of the control unit, the remote server and the portable electronic device.   
     
     
         73 . The method according to  claim 72 , wherein fixing the wearable EGFET to the skin of the subject comprises directly contacting the first microneedle with the skin of the subject, and wherein the measuring step is performed while the wearable EGFET is fixed to the skin of the subject, and/or wherein analyzing the electrical signal comprises comparing the electrical signal with a calibration curve and/or reference data, and/or wherein the method further comprises displaying information related to the measuring of the electrical signal or a result of the step of analyzing (step (d)) onto a display unit being in electrical communication with the control unit, the remote server, or the portable electronic device. 
     
     
         74 . A method for fabricating the wearable EGFET device according to  claim 49 , the method comprising:
 (a) providing the first microneedle, the first electric contact, and the polymeric substrate;   (b) providing the FET;   (c) connecting the first electric contact with the polymeric substrate;   (d) connecting the first microneedle with the polymeric substrate; and   (e) associating the FET with the first microneedle.   
     
     
         75 . The method according to  claim 74 , wherein steps (a), and (b) are performed in any order or wherein at least two of said steps are performed simultaneously, or wherein the method further comprises a step of providing the second microneedle and the second electric contact, and a step of connecting the second microneedle and the second electric contact with the polymeric substrate. 
     
     
         76 . The method according to  claim 75 , wherein providing the first electric contact and/or providing the second electric contact comprises spray-coating hydrophobic electrically conductive elongated nanostructures onto a Si wafer coated with a mask having a predefined opening, peeling the mask and annealing the obtained first electric contact and/or second electric contact. 
     
     
         77 . The method according to  claim 74 , wherein providing the polymeric substrate comprises forming a first substantially flexible and stretchable polymeric film and combining said film with a second substantially flexible and stretchable polymeric film, which has been pre-stretched, and/or wherein providing the polymeric substrate comprises thickening a portion of the polymeric substrate by applying a solution of the substantially flexible and stretchable polymer onto said portion. 
     
     
         78 . The method according to  claim 77 , wherein the step of connecting the first electric contact with the polymeric substrate comprises spin-coating a solution of the substantially flexible and stretchable polymer onto the first electric contact to form the first substantially flexible and stretchable polymeric film prior to combining said first substantially flexible and stretchable polymeric film with the second substantially flexible and stretchable polymeric film, which has been pre-stretched, and/or wherein the step of connecting the first microneedle with the polymeric substrate comprises fixing the first microneedle onto the thickened portion of the polymeric substrate.